RESUMEN
The anticonvulsant carbamazepine 1 is associated with adverse drug reactions (ADRs), including hepatotoxicity; oxidative metabolism of 1 has been implicated in the pathogenesis of the ADRs. We report the synthesis and evaluation of 2-monohalo and 2,8-dihalo analogues of 1 that were intended to minimize reactive metabolite formation via arene oxidation and 10,11-epoxidation. Halo analogues were obtained either by rearrangement of halogenated N-arylindoles or from specifically halogenated iminodibenzyl derivatives. In rat hepatocytes, none of the analogues underwent oxidative dehalogenation or glutathione adduction. Some formation of the 10,11-epoxide still occurred, but aromatic hydroxylation was not seen with the exception of 2-fluoro, which allowed minor monohydroxylation. Complete inhibition of aromatic hydroxylation required at least monochlorination or difluorination of 1. In human liver microsomes, difluoro analogue 5b underwent 10,11-epoxidation but gave no arene oxidation.
Asunto(s)
Anticonvulsivantes/farmacología , Carbamazepina/análogos & derivados , Halógenos/química , Hepatocitos/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Animales , Anticonvulsivantes/síntesis química , Carbamazepina/farmacología , Células Cultivadas , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Glutatión/metabolismo , Hepatocitos/metabolismo , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Estructura Molecular , Oxidación-Reducción , Ratas , Ratas Wistar , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Relación Estructura-ActividadRESUMEN
Efficient procedures for the synthesis of benzo-fluorinated dibenz[b,f]azepines (iminostilbenes) from fluorinated isatins or indoles using a number of ring-expansion reactions are described. A range of mono- and difluorinated analogues is accessible, and the syntheses can deliver gram quantities of the final products, which are precursors of fluoro analogues of the important anticonvulsant carbamazepine.